Valve treatment catheter and methods

ABSTRACT

The invention provides a catheter for insertion into a biological passage which contains a first flowing fluid, the catheter including a tubular member having a proximal end and a distal end; a fluid delivery lumen contained within the tubular member; an inflatable balloon assembly disposed at the distal end of the tubular member, the balloon assembly including an inflatable balloon member having an uninflated state and an inflated state, the balloon assembly including apertures in communication with the fluid delivery lumen; an inflation lumen in communication with the balloon member; and a valve contained within the inflatable balloon assembly. The inflatable balloon is assembly configured such that when the balloon member is in the inflated state: (i) sections of the balloon member contact the biological passage defining at least one containment pocket; (ii) the apertures are disposed in the containment pocket, (iii) a flow lumen is defined through the balloon member to allow the first fluid to flow through the balloon member; and (iv) the valve functions to allow the first flowing fluid to flow through the flow lumen in a physiologic direction, while blocking backflow of the first fluid through the flow lumen.

FIELD OF THE INVENTION

The invention relates to treatment of a biological passage containing avalve. More particularly, the invention provides a catheter having ablood flow lumen containing a valve that mimics the native valve to betreated. The valve of the inventive device permits blood flow in aphysiologic direction while blocking backflow.

BACKGROUND OF THE INVENTION

Heart valve disease is a serious health problem facing society today.There are approximately 225,000 surgeries annually to repair damagedheart valves. Of these surgeries, at least 60,000 Americans receivereplacements for valves damaged by congenital or rheumatic heartdisease.

Cardiac valves have three functional properties: (1) preventingregurgitation of blood flow (also referred to as retrograde flow, orbackflow) from one chamber to another, (2) permitting rapid flow ofblood without imposing resistance on that flow, and (3) withstandinghigh-pressure loads. Importantly, all four of the heart valves arepassive structures in that they do not themselves expend any energy anddo not perform any active contractile function. They consist of movableleaflets that are designed simply to open and close in response todifferential pressures on either side of the valve. Fluid flows fromareas of high pressure to areas of low pressure. In the heart, thevalves open and close in response to pressure gradients; that is, valvesopen when pressure in the preceding chamber is higher and close when thegradient reverses.

Because proper valve function is an important aspect of the presentdisclosure, basic cardiac physiology will be described in some detailwith reference to FIGS. 1 and 2. FIG. 1 shows a cross-sectional cutawaydepiction of a normal human heart 91. The left side of the heart 91contains left atrium 93, left ventricular chamber 95 positioned betweenleft ventricular wall 97 and septum 99, aortic valve 101, and mitralvalve assembly 103. The components of the mitral valve assembly 103include the mitral valve annulus 105, anterior leaflet 107 (sometimesreferred to as the aortic leaflet, since it is adjacent to the aorticregion), posterior leaflet 109, two papillary muscles 111 and 113, andmultiple chordae tendineae 115. The papillary muscles 111 and 113 areattached at their bases to the interior surface of the left ventricularwall 97. The chordae tendineae 115 couple the mitral valve leaflets 107and 109 to the papillary muscles 111 and 113, and these cords supportthe mitral valve leaflets and control or restrict leaflet motion.

The right side of the heart contains the right atrium 121, a rightventricular chamber 123 bounded by right ventricular wall 125 and septum99, and a tricuspid valve assembly 127. The tricuspid valve assembly 127comprises a valve annulus 129, three leaflets 131, papillary muscles 133attached to the interior surface of the right ventricular wall 125, andmultiple chordae tendineae 135. The chordae tendineae 135 couple thetricuspid valve leaflets 131 to the papillary muscles 133 and servesimilar function as for the mitral valve leaflets.

Turning to the two cardiac valves that function to permit blood flow outof the heart to the lungs (the pulmonary valve) or to the aorta (aorticvalve), reference will now be made to FIG. 2. FIG. 2 shows across-sectional cutaway depiction of a normal heart 91, illustrating thefour valves of the heart, namely the mitral valve assembly 103,tricuspid valve assembly 127, pulmonary valve 151, and aortic valve 161.The aortic valve 161 and pulmonary valve 151 are referred to assemilunar valves because of the unique appearance of their leaflets,which are more aptly termed cusps and are shaped like a half-moon. Eachof the semilunar valves includes three cusps, and neither of the valvesincludes associated chordae tendineae or papillary muscles.

The aortic valve includes cusps 163, 165, and 167 that respond topressure differentials between the left ventricle and the aorta. Whenthe left ventricle contracts, the aortic valve cusps 163, 165 and 167open to allow the flow of oxygenated blood from the left ventricle intothe aorta. When the left ventricle relaxes, the aortic valve cuspsreapproximate to prevent the blood that has entered the aorta fromleaking (regurgitating) back into the left ventricle. The pulmonaryvalve includes cusps 153, 155, and 157 that respond passively in thesame manner in response to relaxation and contraction of the rightventricle in moving de-oxygenated blood into the pulmonary artery andthence to the lungs for re-oxygenation.

The valves in the heart thus maintain the physiologic direction of bloodflow, namely: right atrium-right ventricle-lungs-left atrium-leftventricle-aorta. Although each of these valves has slightly differentstructure, they serve similar functions. When the ventricle expands, theatrioventricular valve allows blood to flow forward from the atrium intothe ventricle while the semilunar valve keeps blood that has alreadybeen pumped out of the heart from flowing back in. Conversely, when theventricle contracts, the atrioventricular valve closes to preventbackflow while the semilunar valve opens to allow blood to be pumpedeither to the body or the lungs. The prevention of backflow ensures theproper direction of flow through the circulatory system and reduces theamount of work the heart must do to pump blood through the system.

There are numerous complications and diseases of the heart valves thatcan prevent the proper flow of blood. Heart valve disease can beclassified into one of two categories: stenosis (or hardening of thevalve), and incompetence (or permittence of backflow). Stenotic valvescannot open fully, requiring more work to push the liquid through thevalve. By contrast, incompetent valves waste work by allowing blood toflow backward (backflow). As a result of stenosis or incompetence, theheart must work harder to provide the same level of blood circulation,and in many cases the heart becomes incapable of sustaining an activelifestyle.

Though the causes of heart valve disease are numerous, there are threeprincipal culprits. Rheumatic fever stiffens valve tissue, causingstenosis. Congenitally defective valves do not form properly as theheart develops, but often go unnoticed until adulthood. Bacterialinfection of the heart can cause inflammation of valves, tissuescarring, or permanent degradation. Many of these damaged valves have tobe replaced in order for the patient to live a normal life, since thestrain on their heart would otherwise cause such symptoms as chest pain,fatigue, shortness of breath, and fluid retention.

Once a cardiac valve is damaged, treatment options include replacementof the damaged valve or pharmacologic intervention. Current options forreplacing heart valves include mechanical prosthetics, bioprosthetics,and transplants. While each of these options has benefits, there aredrawbacks associated with each.

Mechanical prosthetic heart valves mimic the function of natural heartvalves with a variety of artificial structures. The majority of currentmechanical valve designs, and those that are considered closest tonative valves, constitute bileaflet valves. These valves consist of twosemicircular leaflets (often fabricated from carbon) that pivot onhinges. The carbon leaflets exhibit high strength and excellentbiocompatibility. The leaflets open completely, parallel to thedirection of blood flow. However, the mechanical leaflets do not closecompletely, which allows some backflow. Since backflow is one of theproperties of defective valves, the bileaflet valves are still not idealvalves. As a result of the less-than-ideal flow properties of the valve,these valves can cause the heart to work harder to pump blood. Theresulting stress on the heart can damage heart muscle and blood cells inthe vicinity of the valve. In addition, mechanical valves can causethrombosis, or blood clot formation, and serve as excellent substratesfor bacterial infection. Thus, recipients of these medical valves areoften required to take anticoagulants, or blood clot inhibitors, for therest of their lives.

Although effective for short relatively short periods (typically ten tofifteen years), bioprosthetic valves offer a second alternative forsuccessfully replacing human valves. Generally, bioprosthetic valves arevalves made from tissue harvested from other mammals. The most commonlyused animal tissues for bioprosthetic valves are porcine (pig) andbovine (cow) pericardial tissue. The harvested porcine or bovine tissueis treated with a fixative (often glutaraldehyde) before implantation.The most common cause of bioprosthesis failure is stiffening of thetissue due to the build up of calcium. Calcification can cause arestriction of blood flow through the valve (stenosis) or cause tears inthe valve leaflets, thereby requiring a subsequent valve replacement.Further, bioprosthetics generally do not integrate well with the hostorganism and eventually die.

The third alternative is a transplant from a human organ donor. In thiscase, the replacement valve becomes a living part of the surroundingheart tissue, if it can overcome the initial immune system rejectionseen in all human-to-human transplants. However, this alternative is notcommonly seen, since most available human hearts are directed towhole-heart transplants, rather than valve-only transplants.

The alternative to replacement of the damaged valve is treatment of thevalve with therapeutic agents. Delivery of a therapeutic agent to thevalve tissue can result in improved valve function, and correspondingly,improved heart function. Generally, pharmacologic treatment is systemic.That is, a therapeutic agent is orally or intravenously injected intothe patient and is therefore delivered throughout the patient's entirebody. In the case of systemic treatment, high concentrations of thetherapeutic agent cannot be used in many cases, because of risk ofundesirable side effects.

Thus, current treatment options for heart valve disease have severaldrawbacks. Damaged or diseased heart valves can be replaced with one ofseveral different types of prosthetic valves. These prosthetic valvesmust create a non-return flow system and must meet certain standardswith regard to strength and durability, since the human body is a harshplace for foreign objects. Alternatively, damaged or diseased heartvalves can be treated with therapeutic agents. Although therapeutictreatment is a preferred alternative to outright replacement of thevalve, risks associated with systemic exposure to the therapeuticagent(s) must be taken into consideration.

For treating vessel walls, a flow through catheter has been developedthat merely provides flow through while exposing the vessel walls to atherapeutic agent. U.S. Pat. No. 5,558,642 (the entire disclosure ofwhich is incorporated herein by reference) describes a drug deliverycatheter that can be inserted into a vessel, such as a blood vessel. Thedrug delivery catheter comprises an elongated tubular shaft thatincludes a drug lumen for delivering a drug to the treatment site and auniquely configured inflatable balloon assembly. The balloon assembly isdisposed at the distal end of the shaft and includes an inflatableballoon member. The balloon member has a configuration such that whenthe balloon member is uninflated, the fluid in the vessel (such asblood) may flow around the balloon assembly. This provides anarrangement that may be easily inserted and manipulated through thevascular system. When the balloon member is in an inflated state, partof the balloon member contacts the vessel wall defining a containmentpocket between the vessel wall and the balloon assembly. The balloonassembly includes apertures in the containment pocket that are in fluidcommunication with a drug lumen in order to provide the drug to thecontainment pocket. A flow lumen is also defined through the balloonmember when it is inflated in order to allow the fluid in the vessel,such as blood, to flow through the balloon assembly. The catheter alsoincludes an inflation lumen that is used to inflate the balloon member.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a catheter for insertion into abiological passage which contains a first flowing fluid, the cathetercomprising: a tubular member having a proximal end and a distal end; afluid delivery lumen contained within the tubular member; an inflatableballoon assembly disposed at the distal end of the tubular member, theballoon assembly including an inflatable balloon member having anuninflated state and an inflated state, the balloon assembly includingapertures in communication with the fluid delivery lumen; an inflationlumen in communication with the balloon member; and a valve containedwithin the inflatable balloon assembly. According to the invention, theinflatable balloon assembly is configured such that when the balloonmember is in the inflated state: (i) sections of the balloon membercontact the biological passage defining at least one containment pocket;(ii) the apertures are disposed in the containment pocket, (iii) a flowlumen is defined through the balloon member to allow the first fluid toflow through the balloon member; and (iv) the valve functions to allowthe first flowing fluid to flow through the flow lumen in a physiologicdirection, while blocking backflow of the first fluid through the flowlumen.

In another aspect, the invention provides a catheter for insertion intoa biological passage which contains a first flowing fluid, the cathetercomprising: a tubular member having a proximal end and a distal end; aninflatable balloon assembly disposed at the distal end of the tubularmember, the balloon assembly including an inflatable balloon memberhaving an uninflated state and an inflated state; an inflation lumen incommunication with the balloon member; and a valve contained within theinflatable balloon assembly. According to this aspect, the inflatableballoon assembly is configured such that when the balloon member is inthe inflated state: (i) sections of the balloon member contact thebiological passage defining at least one containment pocket; (ii) a flowlumen is defined through the balloon member to allow the first fluid toflow through the balloon member; and (iii) the valve functions to allowthe first flowing fluid to flow through the flow lumen in a physiologicdirection, while blocking backflow of the first fluid through the flowlumen.

In yet another aspect, the invention provides a catheter for insertioninto a biological passage which contains a first flowing fluid, thecatheter comprising: a tubular member having a proximal end and a distalend; a fluid delivery lumen contained within the tubular member; aninflatable balloon assembly comprising a first toroidal-shaped balloondisposed at the distal end of the tubular shaft, a secondtoroidal-shaped balloon spaced proximally from the first toroidal-shapedballoon, and a cylindrical sheath attached to the first and secondtoroidal-shaped balloons, wherein the first and second toroidal shapedballoons have an outer diameter, and wherein the sheath is attached tothe toroidal-shaped balloons at a position radially inward of the outerdiameter of the toroidal-shaped balloons; an inflation lumen incommunication with the toroidal-shaped balloons; and a valve containedwithin the sheath, wherein the inflatable balloon assembly is configuredsuch that when the toroidal-shaped balloons are inflated: (i) thetoroidal-shaped balloons expand the sheath, (ii) sections of thetoroidal-shaped balloons contact the biological passage wall defining atleast one containment pocket between the biological passage, the tubularshaft, the toroidal-shaped balloons, and the sheath; (iii) the aperturesare disposed in the containment pocket, (iv) the sheath forms a flowlumen to allow the first fluid to flow through the balloon member; and(v) the valve functions to allow the first flowing fluid to flow throughthe flow lumen in a physiologic direction, while blocking backflow ofthe first fluid through the flow lumen.

In yet another aspect, the invention provides a method of delivering atherapeutic fluid to a treatment site in a biological passage, thetreatment site including a valve, the biological passage containing afirst fluid, the method comprising steps of: providing an inflatableballoon assembly on the distal end of a catheter, the size of theballoon assembly when deflated adapted to fit within the biologicalpassage; positioning the balloon assembly at the treatment site;inflating the balloon assembly at the treatment site; engaging a sectionof the biological passage with a section of the balloon assembly whilemaintaining a section of the balloon assembly away from the biologicalpassage thereby defining a plurality of containment pockets within theengaging section; and delivering a therapeutic fluid to the containmentpockets, wherein when the balloon assembly is inflated, the balloonassembly defines a flow lumen through which the first fluid can flow,while maintaining the therapeutic fluid within the containment pockets,and a valve contained within the balloon assembly functions to allow thefirst flowing fluid to flow through the balloon member in a physiologicdirection, while blocking backflow of the first fluid through theballoon member.

The invention provides improved devices and methods for effectivelytreating a biological passage containing a valve. Preferred embodimentsof the invention can be advantageously used to provide flexibility intreatment duration and type of therapeutic agent delivered capable ofbeing delivered to a native valve.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated in and constitute apart of this specification, illustrate several aspects of the inventionand together with the description of the preferred embodiments, serve toexplain the principles of the invention. A brief description of thedrawings is as follows:

FIG. 1 is a cross-sectional view of a normal human heart.

FIG. 2 is a cross-sectional view of a normal human heart, illustratingthe four heart valves.

FIG. 3 is a perspective view of an embodiment of a catheter of theinvention.

FIG. 4 is an exploded view in perspective of the distal portion of theembodiment shown in FIG. 3.

FIG. 5 is a side view of another embodiment of a catheter of theinvention in a deflated state, shown within a biological passage.

FIG. 6 is a cross-sectional view of a catheter of the invention, showninserted in an uninflated state into a biological passage.

FIG. 7 is a cross-sectional view of the embodiment shown in FIG. 6,wherein the catheter is inserted into a biological passage and is in aninflated state.

FIG. 8 is a cross-sectional view of the embodiment shown in FIG. 7.

FIG. 9 is a side view of an embodiment of the invention.

FIG. 10 is a cross-sectional view of the embodiment shown in FIG. 9.

FIG. 11 shows a front view of the embodiment shown in FIG. 9.

FIG. 12 is a top view of one embodiment of a valve of the invention.

FIG. 13 is a side view of another embodiment of a valve of theinvention.

FIG. 14 is a side view of another embodiment of a valve of theinvention.

DETAILED DESCRIPTION OF THE INVENTION

The embodiments of the present invention described below are notintended to be exhaustive or to limit the invention to the precise formsdisclosed in the following detailed description. Rather, the embodimentsare chosen and described so that others skilled in the art canappreciate and understand the principles and practices of the presentinvention.

The present invention is directed to methods and apparatuses foreffectively treating a biological passage, and in particular fordelivering therapeutic agents to a valve within a biological passage.Such methods and apparatuses in accordance with the present inventioncan advantageously be used to provide flexibility in treatment durationand type of therapeutic agent delivered to the valve. In particular, thepresent invention has been developed for delivering one or moretherapeutic agents to a valve while maintaining blood flow through thebiological passage in a physiologic manner. Such devices (for example,catheters), themselves, are known for treating problems and diseases ofthe body in that they are made for introduction within any number ofbody passages or lumens, such as are provided within the vascular,urinary, respiratory, esophageal, gastrointestinal systems of the bodyand the like. Therapeutic catheterization techniques (whether fortreatment of a site or for diagnostic purposes) can involve the use of aguide wire that is first controllably inserted within the body up to andbeyond the treatment site within the body lumen. Thus, in order tofollow such a guide wire to a treatment site, catheter lumens have beendeveloped that comprise one or more tubular components that can be slidalong the guide wire to the appropriate treatment site. As usedthroughout this disclosure, a treatment site can comprise a site that isto receive treatment directly or indirectly from a catheter component orany site that is being diagnosed directly or indirectly by a cathetercomponent.

For example, a balloon catheter for intravascular treatment is typicallydelivered along a guide wire. Balloon catheters are well known, such asare described in U.S. Pat. No. 5,797,878, U.S. Pat. No. 5,931,812 andU.S. Pat. No. 5,948,345, the entire disclosures of which areincorporated herein by reference. A typical balloon catheter has anelongate shaft with an inner tubular lumen and has a dilatation balloonattached proximate the distal end and a manifold attached proximate theproximal end. These catheters are designed for introduction into a bodylumen over the guide wire, which guide wire is slidably received withinthe inner lumen of the catheter. In use, the balloon catheter isadvanced over the guide wire such that the dilatation balloon ispositioned adjacent a treatment site, such as an occlusion or anyobstruction, lesion, or stenosis of a body lumen. Then, fluid underpressure is supplied to the balloon through the catheter lumen,expanding the balloon and thus applying a force to the wall of the bodylumen, such as for opening or otherwise treating or diagnosing it.

In order to be properly introduced, delivered and controlled, cathetersof all sorts of types are preferably designed to accommodate needs forpushability, trackability, crossability and torque transmission to thedistal catheter end as such is applied to the proximal end of thecatheter. For purposes of this application, the following terms aregiven the following meaning. Pushability is the ability to transmitforce from the proximal end of the catheter to the distal end of thecatheter. A catheter shaft should have adequate strength for pushabilityand resistance to buckling or kinking. Trackability is the ability tonavigate tortuous vasculature or other body lumens. That is, the distalportion of the catheter must track the guide wire through small tortuousvessels or body lumens to reach the area to be treated. A more flexibledistal portion is known to improve trackability. Thus, it can bedesirable to provide a catheter shaft with elastomeric properties toimprove flexibility. Crossability is the ability to navigate the ballooncatheter across narrow restrictions or obstructions in the vasculature.

Optimization of pushability, trackability, crossability and torquetransmission can be accomplished by carefully choosing the cathetermaterial and its physical characteristics, such as wall thickness.Because these catheters are frequently inserted for long distances, itis generally also desirable to minimize the friction between the guidewire and the surface of the catheter lumen by constructing the catheterfrom a lubricious material such as a high-density polyethylene (HDPE),polytetrafluoroethylene (PTFE) or similar material. Polymeric materialsare known for these uses.

In order to achieve a combination of desired properties at differentparts of the catheters themselves, catheters have been developed bycombining a plurality of tubing components together to define a catheterlumen. That is, a portion of the overall length of a catheter lumen cancomprise a different tubing type component than another. These one ormore portions can comprise tubing components of different physicalcharacteristics and/or different materials. For example, a tip portioncan be provided that is more resilient than the remainder of thecatheter lumen for better crossability and to provide a softer leadingend of the catheter for abutting internal membranes of the body and thelike. Different materials include different polymeric materials from oneanother, for example, or similar polymers of different densities,fillers, crosslinking or other characteristics. In particular, a portionof a catheter lumen can comprise a material chosen for flexibility tofollow a body lumen's path while another portion can comprise a materialchosen for axial and/or torque transmission.

Likewise, other catheter features, such as balloons, are frequentlyprepared from a variety of polymeric materials depending upon theirintended use. Generally, materials for balloons, for example, arerequired to possess elastomeric properties so that the dilatationballoon has the requisite compliance to achieve a predeterminedrelationship between balloon diameter and dilatation pressure. Moreover,such balloons must be able to resist bursting at the relatively highpressures commonly employed during these procedures. Because commonlyused lubricious catheter materials typically do not possess requisiteelastomeric properties, the balloons are frequently prepared from apolymeric material that is different from, and is not readily bonded to,the material employed to fabricate the catheter. For, example, balloonsare frequently formed from polyethylene terephthalate (PET), as well asnylon.

Catheters can include any number of internal lumens to providefunctionalities to the distal end of the device. Typical lumens includedwithin catheters include a guide wire lumen and an inflation lumen.Generally, the inflation lumen is configured to contain inflation mediumand is in fluid communication with the balloons of the device.

According to the present invention, a catheter has been developed thatcan be used to treat any passage in the body in which it is desirable tocontrol flow of biological fluids during the course of treatment. Inpreferred embodiments, the catheter can be used to provide one or moretherapeutic agents to a treatment site that contains a valve, where itis desirable to maintain fluid flow through the treatment site in aphysiologic direction during the course of treatment. More specifically,the catheter of the invention includes a valve to maintain bodily fluidflow in a single direction. The valve opens and closes with pressureand/or flow changes. The invention can be placed anywhere in the human(or animal) body where flow control is desired. As described herein,flow control at the treatment site can mean control both in direction offluid flow and hemodynamics of that fluid flow. More specifically, thecatheter provides the ability to maintain fluid flow in a physiologicdirection (that is, block retrograde flow through the device). Inaddition, the catheter can preferably maintain proper hemodynamics atthe treatment site by minimizing disruption of fluid flow patternsthrough the biological passage.

To facilitate the discussion of the invention, use of the invention totreat a heart valve will be addressed. Heart valves are selected becausethey provide the highest risk to the patient during treatment. Further,in terms of lowering the risk while providing a superior device, theadvantages of this catheter can be clearly presented. However, it isunderstood that the device and methods disclosed are applicable to anyvalvular needs, for example, treatment of the esophagus or otherbiological passages of the body where controlled flow of biologicalfluids is desired during treatment. Additionally, the inventive deviceand methods are applicable to venous applications (such as, for example,failure of competence of venous valves).

A preferred use for this device is a method of treating a biologicalpassage that contains a valve. It will be understood that the inventivedevice can be used at the location of the natural valve, or at alocation adjacent to the natural valve to be treated. Moreover, theinvention can be used to treat a native valve, or the invention can beused to treat an area surrounding and including a previously implantedprosthetic valve (for example, when therapeutic agent delivery isdesirable after implantation of the prosthetic valve).

With reference to the accompanying FIGS., and initially to FIGS. 3 and4, a catheter 1 in accordance with the invention is illustrated thatincludes a proximal end 4 and distal end 6. The catheter 1 is designedsuch that the distal end 6 is to be inserted into a patient to effecttreatment at a treatment site. At the proximal end 4, controls arelocated to allow the interventionalist to control functionalitieslocated at the distal end. The distal end 6 of the catheter includes aninflatable balloon assembly 5 for treatment of a valve (illustrated inan inflated state in FIGS. 3 and 4).

Referring to FIG. 3, the catheter 1 includes an inflatable balloonassembly 5 at the distal end 6. The balloon assembly 5 includes a singleinflatable balloon member. In an uninflated state, the balloon assembly5 does not significantly increase the overall diameter of the distal end6 of the catheter 1. This allows the distal portion 6 of the catheter tobe inserted into the patient and guided through the patient'svasculature to the desired treatment site. Once at the treatment site,the balloon assembly is inflated. When inflated, the balloon of theballoon assembly 5 impinges upon or engages the biological passage wallat the treatment site. The balloon assembly can include any number ofindividual balloons in a number of configurations, depending upon theparticular treatment site. Some illustrative configurations of theballoon assembly will be described in more detail.

The inflatable balloon portions can be provided in a variety ofconfigurations to engage the biological passage wall at the treatmentsite. For example, FIG. 4 illustrates one embodiment of the balloonassembly, wherein the balloon assembly 5 comprises a single piece ofballoon tubing attached to the tubular member 2 to form toroidal ordonut-shaped balloon portions 9, 11, 13, and 15. As shown in FIG. 4, theballoon tubing can be attached to the tubular member to form a helicalconfiguration of the balloon portions 9, 11, 13, and 15.

Alternatively, the balloon portion(s) of the balloon assembly 5 can beprovided in a non-helical configuration. FIG. 5 illustrates anotherembodiment of the balloon assembly, wherein the balloon assembly 5comprises a single piece of balloon tubing attached to the tubularmember 2 to form a series of toroidal shaped balloon portions 9, 11, 13,and 15. According to this embodiment, the most distal balloon portion 9and the next most distal balloon portion 11 are positioned adjacent toeach other, as are the most proximal balloon portion 15 and the nextmost proximal balloon portion 13. In this embodiment, pairing of theindividual balloon portions at the proximal and distal ends of theballoon assembly advantageously provides two points of anchoring foreach pair of balloon portions. As shown in FIG. 5, the balloon is in anuninflated state.

The inflatable balloon assembly is configured to impinge upon the wallsof the treatment site to allow treatment of a valve while maintainingphysiologic blood flow through the catheter. The number of individualballoon portions comprising the balloon assembly can thus be chosen tocreate a desired number of containment pockets described in more detailbelow. The individual balloon portions of the balloon assembly can beinflated from one or more points. Further, the spacing of the individualballoon portions can be modified as desired, to provide an effectiveamount of contact area with the biological passage wall for treatment.More balloon portions can be located between the previously describedtoroidal-shaped balloon portions 9, 11, 13 and 15, and the balloonassembly can be provided with a single proximal balloon portion andsingle distal balloon portion, as opposed to the dual anchoring assemblydescribed previously. For all of these embodiments, the distance fromthe most proximal balloon portion to the most distal balloon portion ofthe balloon assembly can range from about 10 mm to about 30 mm apart,and the inside balloon portions can be disposed about 2 mm to about 3 mmapart.

In some embodiments, the balloon assembly can include multiple sectionsof inflatable balloon portions. For example, the mid-section of theballoon assembly can comprise balloon portions configured in a helicalmanner about the tubular member of the catheter, while the end sectionsof the balloon assembly can comprise plural distinct balloon portionsconfigured in a non-helical manner about the tubular member. In thisembodiment, the helical balloon portions can act to push the valvetissue evenly against the biological passage wall and allow properfunction of the catheter valve.

In its inflated state, the balloon assembly defines a flow lumen 25(also referred to herein as a perfusion lumen) that permits nativebiological fluid (such as blood) to continue to flow through thecatheter 1 during treatment. As will be described in more detail below,the flow lumen 25 is defined by a sheath 19 that is attached to theballoon portions 9, 11, 13, and 15 of the balloon assembly. Theindividual balloon portions of the balloon assembly thus serve to expandthe sheath 19 and create the flow lumen 25 of the catheter during use.

During use of the inventive device, the flow of blood through the sheath19 can be cut off by one or more of the following: (1) a lesion in thebiological passage can deform the sheath; (2) the device could be placedat a bend in a biological passage, causing the sheath to kink; or (3)the pressure of the fluid containing therapeutic agent could force theflow lumen of the catheter shut. The number of individual balloonportions comprising the balloon assembly, and the spacing between theindividual balloon portions, can be important in maintaining theappropriate blood flow through the biological passage being treated.Therefore, the radial support for sheath 19 needed to maintain the bloodflow lumen 25 through the center of the sheath 19 is provided by theinflatable balloon portions 9, 11, 13, and 15. The differentconfigurations illustrated herein can be used to provide more or lessradial support, as needed. Increasing the number of balloon portions inthe balloon assembly can increase the ability of the balloon assembly tomaintain the perfusion lumen 25 open.

The outside diameter of the inflatable balloon portions 9, 11, 13 and 15in their inflated state is selected to create a suitably sized flowlumen 25 through the catheter, while also allowing a valve (describedbelow) located within the flow lumen to control fluid flow through thecatheter. In an exemplary embodiment, the balloon portions 9, 11, 13,and 15 are about 3 millimeters in outside diameter in their inflatedform. The balloon portions, for example, can have an outside diameterranging about 2 mm to about 22 mm in their uninflated state, dependingupon the different biological passages of the human (or animal) body inwhich the inventive catheter will be used. The size of the balloonportions may also vary for different procedures and/or patients.

The balloon is preferably made of a polyolefin. One preferred polyolefinmaterial is available from E.I DuPont de Nemours and Co. (Wilmington,Del.), under the trade name Surlyn® Ionomer.

An alternative embodiment of the balloon assembly is illustrated inFIGS. 9, 10, and 11, wherein the balloon assembly is formed by sealingan outer cylindrical sheath 51 and an inner cylindrical sheath 53 toeach other at the ends of the sheaths. The cylindrical sheaths 51 and 53are also intermittently sealed to one another at sections 55. Aninflation region or pouch 57 is defined between the two sheaths 51 and53. These seals 55 run along the circumference of the cylindricalsheaths 51 and 53, except that they are not complete in that spaces areleft at certain points to allow the inflation medium to migrate from onepouch formed between the cylindrical sheaths 51 and 53 to anothersimilar pouch.

As shown in FIGS. 9, 10 and 11, cutouts 59 can be provided in theproximal cone section 61 of the sheaths to allow blood to flow throughthe center of these sheaths 51, 53. At the proximal portion of the cone,the outer sheath 51 and the inner sheath 53 come to an outer balloonwaist 61 and an inner balloon waist 63. The outer balloon waist 61 isbonded with an adhesive, such as Tracon®, to an outer shaft 65 and theinner balloon waist 63 is bonded with a similar adhesive to an innershaft 67. The outer and inner shafts are made in a similar fashion tothe embodiments described herein. The inner shaft 67 can define anynumber of lumens, for example a lumen for a guide wire 69, an inflationlumen, and the like.

According to this embodiment, the inflation medium and therapeutic agentmedium are one and the same. When the balloon assembly is inflated, asshown in FIGS. 9, 10 and 11, the outer sheath 51 contacts the wall ofthe biological passage 71 at the areas designed by reference number 73.The contact area 73 is defined by the section of the outer sheath 51that is not bonded to the inner sheath 53. The area 55 where the twosheaths 51, 53 are bonded, however, does not contact the wall of thebiological passage 71. Therefore, a containment pocket or region 11 forthe therapeutic agent is defined in the space between two adjacentcontact areas 73. The outer sheath 51 can be provided with apertures orholes 75 in order to deliver the therapeutic agent to the wall of thebiological passage 71 in the containment pocket 11. These apertures 75allow for permeability of the inflation medium (which contains thetherapeutic agent) out to the wall of the biological passage 71.Preferably, these apertures 75 are about 0.003 inches in diameter andspaced radially at 90° for each containment pocket 11. Here again otherconfigurations can be suitable as well. For example, both the number andpattern of spacings of the apertures in each containment pocket 11defined by adjacent inflation regions or pouches 57 can vary. Thepolymer used to make the outer sheath can either have the apertures 71as discussed above or alternatively can be semi-permeable to theinflation/therapeutic agent medium.

Similar to other embodiments described herein, the position and numberof inflation pouches 57 can vary for different uses. To accomplish this,the seals between the two cylindrical sheaths 51, 53 can have differentconfigurations depending upon what type of lifting and expansion forcewould be required by the desired application of the device.

The embodiment shown in FIGS. 9, 10 and 11 is preferably made by blowingtwo different sheaths, 51, 53, one slightly smaller than the other. Thesecond smaller inner sheath 53 is inserted coaxially inside the outersheath 51. These are then completely sealed distally, creating anocclusive seal 79 between the two sheaths 51, 53. These two sheaths 51,53 can have intermittent seals through the body of the balloon assemblysimilar to what an inflatable air or water mattress would have; theseseals are incomplete in places, allowing the inflation/therapeutic agentmedium to flow throughout the device. In an exemplary embodiment, theseals are 2 to 3 mm apart with a 0.01 inch wide bond. On the proximalend in the cone area 61 of the sheaths 51, 53, there are sealed cutawayportions 59 for blood flow. This sealing is around the cutaway portions59 and allows the blood to flow through cutaway portions 59 while stillmaintaining inflation space 79 in parts of the cone to the body of thecylindrical sheaths. The sealing can be accomplished in a number ofdifferent ways known in the art.

Other embodiments of the invention can employ seals in the balloonassembly that are intermittent forming welds that are similar to spotwelds. In this embodiment, the therapeutic agent/inflation medium is oneand the same, and the medium is delivered to into the balloon assemblyand is delivered to the treatment site via apertures in the outersheath. As with other embodiments described herein, the position andnumber of inflation pouches and/or seals can have multipleconfigurations depending upon the type of lifting and expansion forcedesired for a particular application.

Referring back to FIG. 4, the balloon assembly 5 further includes acylindrical sheath 19 that connects the balloon portions 9, 11, 13, and15. In use, when the balloon portions 9, 11, 13 and 15 are inflated, theballoon portions pull the sheath 19 into an expanded configuration, andthe expanded sheath defines a flow lumen 25 that permits fluid flowthrough the device in a physiologic direction. Attached to the sheathand included within the flow lumen 25 is a valve 81 that permitsphysiologic flow of fluid (such as blood) through the device, whileblocking retrograde flow.

The expanded diameter of the sheath 19 is less than the diameter of theballoon portions. Therefore, when the balloons are inflated, the sheath19 is attached to the balloons at a point radially inward of the outerdiameter of the balloons in order to create a containment pocket 21.Preferably, the sheath 19 is disposed through and connected to theinterior portion of the toroidal-shaped balloon portions. In anexemplary embodiment, the sheath 19 is typically 25 mm from end to endlongitudinally and is preferably about 0.001 inches thick.

In use, the sheath 19 is situated coaxially to a biological passage wall71 (as shown in FIGS. 5-11) and is open at each end, thereby forming apassageway or flow lumen 25 for the blood to flow through when theballoon portions are inflated. Thus, the sheath 19 creates a barrier forseparation of the fluid containing therapeutic agent and the blood. Thesheath 19 is supported or held open by the toroidal-shaped balloonportions 9, 11, 13, and 15 and has the capability of having a relativelylarge expanded internal diameter. For example, the expanded internaldiameter can be about 0.060 inches, providing a large volume of bloodflow. This internal blood flow lumen 25 formed by the sheath 19 has thecapability of being significantly larger than the tubular member 2.

In some embodiments, the geometry of the sheath 19 can be modified toprovide flared or enlarged areas at the proximal end, distal end, orboth the proximal and distal ends, of the sheath. This can optionallyallow a tighter seal of the device around the treatment site (forexample, the area surrounding the valve to be treated).

The sheath 19 can be prepared from a variety of polymeric materials thatprovide elastomeric properties. Preferably, the sheath 19 can be made ofSurlyn® Ionomer. In an alternative preferred embodiment, the sheath 19can be made of a polyester copolymer such as a random copolymer. Therandom copolymer used to make the sheath of the invention can beprepared according to standard procedures from ethylene glycol, and amixture of dimethyl terephthalate and dimethyl isophthalate. As used inthe random copolymer, the ratio of terephthalate to isophthalate in therandom copolymer can be varied over the range of 99:1 to 80:20. Suitablecopolymers are commercially available and are sold under the trade nameSelar® PT, such as Selar® X257, available from E.I. Dupont de Nemoursand Company (Wilmington, Del.). More preferably, the sheath is preparedfrom a material that does not inactivate the therapeutic agent beingdelivered, such as, for example, polypropylene, silicone,silicone-coated surfaces, PTFE, and the like.

The catheter of the invention allows biological fluid (such as blood) toflow through the device during treatment. This is accomplished byproviding a flow lumen through the balloon assembly, so that when theballoon assembly is in its inflated state, the sheath 19 of the balloonassembly 5 defines a flow lumen 25 that permits blood flow therethrough.The flow lumen 25 further includes one or more valve(s) 81 thatpermit(s) blood flow in a physiologic direction while blockingretrograde flow (backflow) of the blood through the flow lumen 25.

In one embodiment, the flow lumen 25 is created by the inflation of theballoon portions 9, 11, 13, and 15 and can be subsequently collapsedupon deflation of the balloon portions 9, 11, 13, and 15 (FIG. 4). Thedimensions of the deflated device will vary depending upon the specificuse contemplated, but suitable sizes range 0.035 inches to 0.1 inches.

Thus, the blood flow lumen 25 is not an integral part of the shaft ofthe device of the invention. Rather, the flow lumen 25 is created byinflation of the balloon portions 9, 11, 13, and 15 of the device. Sincethe blood flow lumen 25 is not an integral part of the shaft, theultimate diameter of the blood flow lumen 25 is not limited by thediameter of the tubular member 2. When the balloon portions 9, 11, 13,and 15 are deflated, the device is collapsed with essentially no bloodflow lumen and is therefore small enough in diameter to be easilymaneuvered through the patient's vascular system. Unlike prior artdevices, when the balloon portions 9, 11, 13 and 15 are inflated, thecross-sectional area of the blood flow lumen 25 is a significantpercentage of the cross-sectional area of the treatment site, such as avalvular area of the heart. It is believed that blood flow through thedevice is about 60% and can be as much as 80% of the blood flow througha healthy valvular area of the heart without the device in place.

With all of the embodiments described herein, because the flow lumen iscreated by the inflatable balloon assembly, blood flow is permittedthrough the flow lumen and the overall device can be kept to a minimalsize. The flow lumen is formed upon inflation of the balloon assemblyand the device is in effect collapsed in its uninflated form. Thisphysical attribute allows the catheter to be of a small diameter when itis inserted into the patient's body and maneuvered to the desiredposition, yet provides a relatively large blood flow lumen when theballoon member is inflated. This inflatable flow lumen allows the sizeof the device to be minimized while the lumen for blood flow ismaximized. Further, the containment pockets allow the therapeutic agentto be kept separate from physiologic blood flow, so that desiredtherapeutic agent can be administered at higher concentrations andlocally at the selected treatment site.

The invention thus provides a catheter for treating a biological passagewhile maintaining blood flow through the device. In addition, theinvention provides a device for delivering one or more therapeuticagents to the treatment site, while maintaining the therapeutic agentseparate from blood flow through the device. This separation of thenative biological fluid (blood) and therapeutic agent is accomplished bycreation of one or more containment pockets using the balloon assemblyof the device.

For purposes of the description herein, reference will be made to“therapeutic agent,” but it is understood that the use of the singularterm does not limit the application of therapeutics contemplated, andany number of therapeutic agents can be provided using the teachingherein. In one illustrative embodiment, the tubular member 2 of thecatheter 1 includes a fluid delivery lumen 3 configured to containtherapeutic agent to be delivered to a treatment site. At its proximalend, the fluid delivery lumen 3 is coupled to a source of therapeuticagent (not shown). At its distal end, the fluid delivery lumen is incommunication with containment pockets created by the device, as willnow be described in more detail.

When inflated, the balloon portions 9, 11, 13 and 15 define a pluralityof containment pockets 21 for containment of one or more therapeuticagents at the treatment site. As described herein, the containmentpocket is a region in the biological passage that is isolated orseparate from the fluid flowing through the flow lumen (for example,blood). Therefore, a fluid containing therapeutic agent can be containedin this containment pocket 21 in the desired concentrations for apredetermined period of time without entering the blood stream duringthat period of time. Any number of containment pockets can be providedby the device, as desired. The particular number of containment pockets21 created by the catheter of the invention will depend upon the numberof balloon portions contained within the balloon assembly.

As illustrated in FIG. 4, when the portions 9, 11, 13, and 15 areinflated, a containment pocket or region 21 is defined between (i) thesheath 19, (ii) the balloon portions 9, 11, 13, and 15 and, and (iii) abiological passage wall. When the balloon portions 9, 11, 13, and 15 areinflated, they in effect form a seal between the biological passage walland the balloon portions 9, 11, 13, and 15. Thus the balloon portionsdefine the outer boundary of the containment pocket 21. The sheath 19,which is attached to the balloon portions 9, 11, 13, and 15, defines therest of the containment pocket 21. In some embodiments, when a singleballoon is provided in a helical configuration about the tubular member2, a continuous spiral containment pocket 21 will be formed by thedevice.

In use, therapeutic agent is carried from the fluid source (not shown),through fluid delivery lumen 3, and into containment pockets 21 througha plurality of apertures 17. The apertures 17 are placed longitudinallyalong the device between balloon portions 9, 11, 13, and 15. Theapertures 17 are preferably placed on both sides of the tubular member 2and preferably are positioned at an area that does not come in contactwith the biological passage wall. Preferably, the apertures areconfigured to minimize damage to tissue at the treatment site. This canbe accomplished by controlling one or more of such factors as the size,spacing, and location of the apertures so as to minimize the pressure oftherapeutic agent as it leaves the apertures.

Preferably, the apertures 17 generally increase in diameter fromproximal to distal end so that uniform flow out of each aperture 17 isachieved. The apertures are preferably sized such that the fluidcontaining therapeutic agent is not pressure injected out of theapertures 17, but rather the tissue at the treatment site is bathed withthe fluid containing therapeutic agent. The size of the apertures willdepend upon the pressure at which the fluid containing therapeutic agentis being provided at the proximal end by the therapeutic medium source(not shown). In an exemplary embodiment, the more proximal apertures 17are about 0.003 inches in diameter and the more distal apertures areabout 0.005 inches in diameter. These apertures 17 are placed about 2 to3 mm apart from each other, as desired.

Preferably, the catheter minimizes tissue damage that can be caused byejection of a high jet stream of a therapeutic agent from the catheter.Thus, the containment pocket 21 created between the sheath 19 and thebiological passage wall 71 is preferably used to bathe the treatmentsite. In some embodiments, the containment pockets are filled with aporous material. In some embodiments, the use of a porous material inthe containment pocket can provide enhanced delivery of the therapeuticagent to the treatment site. Examples of suitable porous materialinclude porous polymers, polyethylene, polypropylene and the like.

Optionally, therapeutic agent can be delivered to the treatment site viaprotuberances that project from the catheter. Examples of suitableprotuberances include needles, spikes, nozzles and microneedles.Protuberances can be provided by any component of the catheter thatcontacts the biological tissue of the treatment site when the balloonassembly is inflated, such as, for example, the sheath, one or more ofthe inflatable balloon portions, or the like.

The catheter of the invention advantageously provides at least one valvethat provides the ability to control the direction of fluid flow throughthe device, as well as the hemodynamics of the fluid flow. Morespecifically, the valve allows blood flow at the treatment site in aphysiologic direction, while effectively blocking retrograde flow (backflow). As illustrated in FIGS. 6-8, a preferred embodiment of theinvention includes a valve 81 located within the inflatable balloonassembly 5. According to this embodiment, valve 81 is attached to theinner surface of sheath 19 and thus extends across the diameter of theflow lumen 25.

Prosthetic valves are well known, and it is understood that the valve ofthe inventive catheter can be provided in a number of embodiments. Thevalve is chosen to provide such physiologic characteristics ashemodynamic performance that approximates the natural state, and reducedrisk of thrombogenicity. Preferably, the device complies with thenatural motion of the tissue with which it is in contact, so thathemodynamics of the treatment site are maintained during a treatmentperiod. The valve can be designed to allow blood flow in a physiologicdirection (that is, forward flow of the blood through the biologicalpassage), block back flow (also referred to as retrograde flow) of bloodthrough the device, and collapse sufficiently to allow the catheter tobe passed through the vasculature to the treatment site. Preferably, thecomponents of the valve (for example, leaflets) are sufficientlyflexible to open and close smoothly, with minimal pressure drop acrossthe valve and without creating undue turbulence or hemolyticallydamaging the blood cells.

The valve is pre-sized to fit within the internal diameter of the sheath19 and thus extend across the diameter of the flow lumen 25. The valvecan thus be fabricated to any desired size, depending upon theparticular application (for example, heart valve, or other biologicalpassage in the body), and particular patient (for example, a youngpatient such as a young child, or an elderly patient).

Although FIGS. 6-8 illustrate valve 81 as being located along the lengthof the sheath 19, the valve 81 can be provided at any position withinthe sheath 19. For example, in some embodiments, positioning the valvein the proximal or distal end of the sheath can improve valve functionand allow for a smaller collapsed profile. When the valve is located ata proximal or distal end of the sheath, the leaflets of the valve canextend beyond the sheath when the sheath is collapsed, thereby providingimproved profile of the collapsed device. The position of the valvewithin the sheath can be such that it is positioned as closely aspossible to the native valve's anatomical position, to provide improvedvalve function during treatment.

According to the invention, the valve is preferably configured topassively respond to differential pressures on either side of the valve.It is contemplated, however, that an active valve could be incorporatedinto the subject design that can further be controllable from theproximal catheter end. Generally, a valve according to the presentinvention comprises an occluder that is moved aside during forward flowof blood through the device, and blocks backflow through the lumen. Thevalve is preferably suitably durable to withstand pressures within thebiological passage to be treated, but flexible enough to move within thedevice to allow blood flow through the flow lumen. Illustrativeembodiments of the valve will now be described in more detail.

As shown in FIG. 12, the valve can be provided in the form of a flexibleleaflet valve 181. The valve shown in FIG. 12 is a tricuspid valve, andas such, it can be used to mimic the aortic valve. In this embodiment,the flexible leaflet valve 181 comprises a generally arcuate centerportion 183 and, optionally a peripheral cuff portion 185. Asillustrated, the center portion 183 of the valve 181 is generallyarcuate in shape and comprises three leaflets 187 as shown, although itis understood that there could be any desired number of leaflets in theflexible valve, preferably, two to four leaflets. When the valveincludes a peripheral cuff portion 185, this cuff portion can be used toattach the valve to the sheath, for example, by suturing, biocompatibleadhesive, or other suitable attachment methods.

The flexible leaflet valve 181 is preferably disposed within the sheath19 with the arcuate portion transverse of and at some acute anglerelative to the plane of the walls of the sheath 19. The diameter of thearcuate portion can be substantially the same as the inside diameter ofthe lumen 25 when the balloon assembly is inflated. In this embodiment,the peripheral cuff portion 185 is disposed substantially parallel tothe walls of the sheath 19. Thus, when the inflatable balloon assembly 5is inflated, the valve 181 is expanded and spans the area of the flowlumen 25 of the device. Conversely, when the inflatable balloon assembly5 is in a deflated state, the valve 181 preferably collapses within theballoon assembly so as to substantially conform to the outer dimensionsof the collapsed balloon assembly. Thus, in a preferred embodiment, theperipheral cuff portion 185 is fabricated of a flexible material, toallow the cuff portion to collapse when the balloon assembly 5 is in anuninflated state. In this way, the valve does not significantly alterthe overall diameter of the device. The peripheral cuff portion 185 canbe fabricated of a suitable flexible material, and the material can bethe same as, or different from, the material used to fabricate theleaflets of the valve.

In some embodiments of the invention, the leaflets of the valve can beattached to the sheath individually. In these embodiments, theperipheral cuff portion 185 is not included in the device. In theseembodiments, the leaflets can be attached to the sheath using sutures,biocompatible adhesive, a combination of the two, or any other suitableattachment mechanism.

Alternatively, the valve can be fabricated to include standardizedleaflet structures utilizing some of the methodologies described in U.S.Pat. No. 5,928,281 (the entire disclosure of which is incorporatedherein by reference). According to this embodiment, a plurality oftissue leaflets are templated and attached together at their tips for adimensionally stable and dimensionally consistent coapting leafletsubassembly. These valves are pre-aligned and stitched together to alignthe entire valve mating or seating surfaces at once. The desired numberof tissue leaflets are obtained, and each leaflet is trimmed to theappropriate desired shape and size for the intended valve use using atemplate, defining a generally straight or linear coapting mating edgehaving opposing ends and a generally arcuate peripheral cusp extendingtherebetween. More particularly, each leaflet is placed on a cuttingboard and the selected template is then placed over the leaflet. Leafletmaterial extending beyond the boundaries of the template is then cutaway using a cutting tool.

Once cut, the leaflets are pre-aligned along with the template. Theleaflets are then attached or stitched together at one end. Althoughthis reference further attaches this subassembly to a wireform and otherstructural components, for purposes of the present invention, thealigned leaflets can be used without additional structural material, andcan be attached directly to the inner surface of the sheath 19, eitherusing a peripheral cuff such as that shown in FIG. 12, or directly tothe sheath 19 without additional structural components.

The material for the leaflets can be a synthetic resin foil inaccordance with the state of the art, preferably a foil of flexiblepolyurethane. Other materials include silicones, Teflon™, and otherpolymers. The majority of the leaflet area consists of a thin membrane.In some embodiments, the area of the leaflets forming the commissuralareas is more rigid, to provide added support for the valve leaflets. Insome embodiments, mammalian tissue (such as porcine or bovinepericardium, or the like) can be used to form the leaflets.

Preferably, the material used to make the leaflets is matched so thatall leaflets for fabricating a single valve, whether aortic, mitral,semilunar, or the like, are made of material having about the sameresistance to stretching in the circumferential direction, that is,within about 10% of one another, or preferably within about 5% of oneanother.

Optionally, at least a portion of one or more of the leaflets can beinflatable. The leaflet or leaflets can be provided with an inflationlumen that is separate from, or the same as, the inflation lumenutilized for the inflatable balloon assembly. Such an inflatable leafletor leaflets can be functionally connected with any inflation lumen by aflexible conduit or the like that also facilitates its movement away andback toward the collar. It will be appreciated that the provision of anynumber of catheter lumens can be constructed in accordance withwell-known technique, and, as such, need not be discussed in more detailherein. In some embodiments, one or more of the leaflets are entirelyinflated during application of the device. According to theseembodiments, an inflated leaflet can create a better seal than leafletsthat are not inflated. In some embodiments, only a portion of theleaflet is inflatable. According to these particular embodiments,partial inflation (for example, of the edge of the leaflet) can allowfor control of mechanical properties of the leaflet and can lead tobetter function of the leaflet. Inflation of a portion or all of theleaflet or leaflets after placement of the catheter at a treatment sitecan allow the leaflet(s) to be compliant and smaller prior to placementof the device. When the leaflet(s) is in an uninflated state, therefore,the leaflet(s) would not significantly alter the overall dimensions ofthe inventive device. When the leaflet(s) is provided in an inflatedstate, during treatment of a biological passage, the leaflet(s) can beinflated to a desirable size to function as a replacement valve duringthe treatment period.

Optionally, the valve further comprises one or more cord-like structuresto control or restrict leaflet motion. These cord-like structures canprovide function similar to native chordae tendineae in the mitral andtricuspid valve assemblies. Preferably, these cord-like structures serveto attach the leaflets to the sheath 19 and prevent the leaflets fromprolapsing during function of the valve. Suitable materials forfabricating these cord-like structures are durable to anchor theleaflets to the sheath, are sufficiently firm to provide support for theleaflets, and are sufficiently flexible to allow proper functioning ofthe valve according to the invention. The cord-like structures can befabricated, for example, from such materials as_Kevlar™, polyethylene,polyurethane, polypropylene, stainless steel, nitinol, and other likematerials.

As illustrated in FIG. 13, the valve can alternatively be provided inthe form of a ball valve 281. According to this embodiment, the valve281 comprises a collar 283 on the inner surface of the sheath 19 thatslightly decreases the diameter of the flow lumen 25. At the distal sideof the collar 283 is located a spherical occluder 285. The sphericaloccluder 285 is a blocking device, held in place by a tetheringstructure 287 that attaches the occluder 285 to the collar 283. One ormore tethering structures can be provided to attach the sphericaloccluder to the collar. Examples of tethering structures include cords,wires, hinges, and other tethering mechanisms. Suitable materials forthe tethering structure include Kevlar™, polyethylene, polyurethane,polypropylene, stainless steel, nitinol, and other like materials.

Alternatively, the spherical occluder 285 can be held in place using amesh material (not shown). Preferably, the mesh material is fabricatedfrom hemocompatible, non-thrombogenic material. In some embodiments, themesh can be elastic to aid in the function of the valve. Suitablematerials can be selected from those known in the art.

In use, the spherical occluder 285 is pushed aside by the forward flowof blood, but occludes the lumen of the collar 283 when blood flowsbackward. The function of the valve 281 thus mimics native valvefunction in that the valve 281 passively responds to pressure gradientchanges on either side of the valve. The tethering structure 287 can besufficiently elastic, for example, for maintaining the sphericaloccluder 285 in proximity to the collar 283 and for allowing thespherical occluder 285 to move away from the collar 283 when blood flowsthrough the valve 281 a distance permitted by the length of thetethering structure 287. Otherwise, the tethering structure 287 cancomprise non-extendible material for merely limiting movement away fromthe collar 283 as the spherical occluder 285 would move back and forthunder influence of pressure changes. Any number of such tetheringstructures can be provided based upon desired opening and closingcriterion and valve balance dynamics. Conversely, when the pressuregradient changes and the valve 281 closes in response to the pressurechange, the spherical occluder 285 returns to the collar 283 and therebyoccludes the lumen of the collar to prevent backflow of blood throughthe valve.

The spherical occluder 285 can be provided in the form of a ball, anellipsoid, or any suitable shape that serves to occlude the collar 283during use of the device.

In prior caged ball designs, there were several drawbacks associatedwith the primarily metal device. For example, one drawback seen withcaged ball valves was that collisions with the occluder caused damage toblood cells in the valve area. Further, caged-ball valves were notoriousfor stimulating thrombosis, requiring patients to take lifelongprescriptions of anticoagulants. Further, the caged ball valve wasconstructed primarily of metal, and as such, provided a rigid valvestructure that provided less than satisfactory hemodynamics at thetreatment site.

In contrast, the ball valve 281 contemplated in one embodiment of theinvention is contained within the sheath 19 of the catheter, andtherefore the occluder 285 will not collide with walls of the biologicalpassage being treated. Further, the ball valve 281 is used as atemporary functioning valve, during treatment of a biological passageonly, and it is not meant to be permanently implanted within thepatient. Therefore, risks associated with thrombosis are decreasedcompared with prior devices. Further, the ball valve 281 is fabricatedprimarily of polymeric materials (such as, for example, polyethylene,polyurethane, polystyrene, and the like) and therefore provides a moreflexible valve structure that can more closely mimic native valvefunction.

The spherical occluder preferably comprises an inflatable device. Theinflation lumen used to inflate the spherical occluder can be the sameas, or different from, the inflation lumen used to inflate the balloonassembly 5. Such an inflatable occluder can be functionally connectedwith any inflation lumen by a flexible conduit or the like that alsofacilitates its movement away and back toward the collar. It will beappreciated that the provision of any number of catheter lumens can beconstructed in accordance with well-known technique, and, as such, neednot be discussed in more detail herein. When the spherical occluder isin an uninflated state, therefore, the occluder would not significantlyalter the overall dimensions of the inventive device. When the sphericaloccluder is provided in an inflated state, during treatment of abiological passage, the spherical occluder can be inflated to adesirable size to function as a replacement valve during the treatmentperiod.

Thus, in a preferred embodiment, the collar 283 is fabricated of aflexible material, to allow the collar to collapse when the balloonassembly 5 is in an uninflated state. In this way, the valve does notsignificantly alter the overall diameter of the device. The collar 283can be fabricated of a suitable flexible material, and the material canbe the same as, or different from, the material used to fabricate thespherical occluder of the valve.

In another embodiment, illustrated in FIG. 14, the valve can be providedin the form of a flap valve 381. According to this embodiment, the flapvalve 381 comprises a collar 383 on the inner surface of the sheath 19.The collar 383 serves to decrease the diameter of the flow lumen 25. Aflap 385 is attached to the distal side of the collar 383. The flap 385is a blocking device, held in place by a tethering structure 387 thatattaches the flap 385 to the distal side of collar 383. One or moretethering structures can be provided to attach the flap 385 to thecollar in a similar sense as that described above for use with aspherical occluder 285.

In use, the flap 385 is pushed aside by the forward flow of blood, butoccludes the lumen of the collar 383 when blood flows backward. Functionof the flap 385 is similar to that described for the ball valveillustrated and described herein.

The flap 385 can be provided in the form of a disc, cone, or anysuitable shape that serves to occlude the collar 383 during use of thedevice. Further, when the flap 385 is provided in the form of a disc,the disc can include one or more parts. As with all of the contemplatedvalve designs, it is preferable that the flap 385 also be expandable andcollapsible with the sheath 19. In this regard, folding techniques, theuse of elastic elements, and the like are contemplated.

When the catheter includes more than one flap 385, each disc can beseparately attached to the collar 383. Optionally, one or more of theflaps can be inflatable. As described above for the leaflet valve, theflap(s) can be partially or totally inflatable. Reference is made to theprior discussion of leaflet valves for inflatable features. Optionally,the flap can be hinged at one point, to provide desired range of motionof the flap in use. Further, the flap can be designed from elasticmaterials, so that it occludes the lumen in its relaxed state (that is,when the flap occludes the lumen of the collar when flood flowsbackward).

In a preferred embodiment, the collar 383 is fabricated of a flexiblematerial, to allow the collar to collapse when the balloon assembly 5 isin an uninflated state. In this way, the valve does not significantlyalter the overall diameter of the device. The collar 383 can befabricated of a suitable flexible material, and the material can be thesame as, or different from, the material used to fabricate the flap(s)of the valve.

The invention provides a device and methods of providing therapeuticagent to a treatment site while maintaining proper flow of biologicalfluids through the treatment site, as well as isolating therapeuticagent from the flow of native biological fluids through the device. Thetherapeutic agent is provided to the treatment site in a therapeuticallyeffective amount and concentration for the desired treatment. Forexample, 100 mcg/ml of heparin can be used as disclosed in “Effect ofControlled Adventitial Delivery on Smooth Muscle Cell Proliferation: byEdelman et al., Proc. Natl. acad. Sic. (USA) 1990; 87:3773-3778, whichis incorporated herein by reference. Another exemplary therapeutic agentis one or more decalcifying agents, for example, sodium-EDTA(sodium-ethylenediaminetetraacetic acid).

The therapeutic agent is provided at a pressure ranging from a minimalvalue over local blood pressure to 50 pound per square inch (psi),depending upon the volume and concentration of therapeutic agentdesired. Other pressures are contemplated for other uses as per theflexible nature of this device.

The blood in the biological passage continues to flow through the flowlumen created through the center of the sheath. Since the flow lumencreated through the sheath is relatively large (compared to the size ofthe biological passage), the interruption of blood flow through thebiological passage is minimized. Further, since the blood flow isisolated from the containment pocket, the therapeutic agent is onlyadministered locally and does not enter the blood stream until theballoons are deflated (if at all). This allows for the therapeutic agentto be provided to the biological passage wall in high concentrationswithout providing a high concentration of the therapeutic agent in thebloodstream. After the therapeutic agent has been administered to thebiological passage wall for the desired time, the device is removed.Because of the large volume of blood flow accommodated by thisinvention, numerous applications of the therapeutic agent can beeffected without removing the therapeutic agent delivery device for arelatively long period of time, for example, for 15 minutes.

The invention thus provides a catheter that provides aninterventionalist with flexibility as to the duration of treatment of avalvular site, the amount and type of therapeutic agent administereddirectly to the site (without concerns associated with systemicdelivery), and the number of administrations of therapeutic agents(either simultaneously (as in the case of a single medium carrying morethan one therapeutic agents) or sequentially (as in the case of multipleadministrations of single therapeutic agents).

As used herein, “therapeutic agent” refers to an agent that affectsphysiology of biological tissue. In a broad sense, therapeutic agentscan be non-genetic agents, genetic agents, or cellular material.

Examples of non-genetic therapeutic agents include, but are not limitedto, anti-thrombogenic agents, anti-proliferative agents,anti-inflammatory agents, antineoplastic agents, anesthetic agents,anti-coagulants, vascular cell growth promoters, vascular cell growthinhibitors, decalcifying agents, and cholesterol-lowering agents.

Examples of anti-thrombogenic agents include heparin, heparinderivatives, urokinase, and PPack (dextrophenylalanine proline argininechloromethylketone).

Examples of anti-proliferative agents include enoxaprin, angiopeptin,monoclonal antibodies capable of blocking smooth muscle cellproliferation, hirudin, and acetylsalicylic acid.

Examples of anti-inflammatory agents include dexamethasone,prednisolone, corticosterone, budesonide, estrogen, sulfasalazine, andmesalamine.

Examples of antineoplastic agents include paclitaxel, 5-fluorouracil,ciplatin, vinblatine, vincristine, epothilones, endostatin, angiostatin,and thymidine kinase inhibitors.

Examples of anesthetic agents include lidocaine, bupivacaine, andropivacaine.

Examples of anti-coagulants include D-Phe-Pro-Arg chloromethylketone, anRGD peptide-containing compound, heparin, antithrombin compounds,platelet receptor antagonists, anti-thrombin antibodies, anti-plateletreceptor antibodies, acetylsalicylic acid, prostaglandin inhibitors,platelet inhibitors and tick antiplatelet peptides.

Examples of vascular cell growth promoters include growth factorinhibitors, growth factor receptor antagonists, transcriptionalactivators, and translational promoters.

Examples of vascular cell growth inhibitors include growth factorinhibitors, growth factor receptor antagonists, transcriptionalrepressors, translational repressors, replication inhibitors, inhibitoryantibodies, antibodies directed against growth factors, bifunctionalmolecules consisting of a growth factor and a cytotoxin, bifunctionalmolecules consisting of an antibody and a cytotoxin.

Examples of decalcifying agents include ethylenediaminetetraacetic acid(EDTA) and the like.

Examples of cholesterol-lowering agents include vasodilating agents andagents that interfere with endogenous vascoactive mechanisms.

In some embodiments, the therapeutic agent can comprise geneticmaterial. For purposes of the present invention, genetic materialincludes nucleic acid, such as DNA or RNA, that encodes an agent ormolecule of interest. For example, the genetic material can includeanti-sense DNA or RNA. Alternatively, the genetic material can includeDNA coding for any of the following: anti-sense RNA, tRNA or rRNA toreplace defective or deficient endogenous molecules, angiogenic factors,cell cycle inhibitors (including cell differentiation inhibitors and thelike), agents that interfere with cell proliferation (includingthymidine kinase and the like), and bone morphogenic proteins. Examplesof angiogenic factors include, but are not limited to, growth factorssuch as acidic and basic fibroblast growth factors, vascular endothelialgrowth factor, epidermal growth factor, transforming growth factor α andβ, platelet-derived endothelial growth factor, platelet-derived growthfactor, tumor necrosis factor α, hepatocyte growth factor, and insulinlike growth factor.

Examples of bone morphogenic proteins (BMP) include, but are not limitedto BMP-2, BMP-3, BMP-4, BMP-5, BMP-6 (Vgr-1), BMP-7 (OP-1) BMP-8, BMP-9,BMP-10, BMP-11, BMP-12, BMP-13, BMP-14, BMP-15, AND BMP-16. Preferredbone morphogenic proteins include BMP-2, BMP-3, BMP-4, BMP-5, BMP-6, andBMP-7. These dimeric proteins can be provided as homodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively, or in addition, molecules capable of inducingan upstream or downstream effect of a bone morphogenic protein can beprovided. Such molecules include any of the “hedgehog” proteins, or thenucleic acid encoding them.

In some embodiments, the therapeutic agent can comprise cellularmaterial. Such cellular material can be of human origin (autologous orallogeneic) or from an animal source (xenogeneic). The cellular materialcan comprise genetically engineered material designed to deliverproteins of interest at the treatment site.

Exemplary cellular material includes stem and progenitor cells,including side population cells, lineage negative cells (lin−), bonemarrow derived stem cells such as CD34+ and CD34− cells, cKit+ cells,mesenchymal stem cells, embryonic stem cells, fetal or neonatal cells,cord blood cells, cardiac-derived stem cells, fat-derived stem cells,and endothelial progenitor cells. Other exemplary cells include cellsfrom whole blood marrow; bone marrow mononuclear cells; muscle-derivedcells such as skeletal myoblasts (satellite cells), adultcardiomyocytes, “go cells”, and other muscle-derived cells (MDCs);endothelial cells; fibroblasts (for example, myoD scar fibroblasts);smooth muscle cells; genetically modified cells such as pacing cells;cloned cells such as embryonic stem cell clones; immunologically maskedcells; teratoma-derived cells, and cell populations that have beentreated with differentiation or growth factors, such as mesenchymalcells or fibroblasts that have been treated with 5-aza. Also includedare tissue engineered grafts, for example isolated cells that have beengrafted onto resorbable scaffolds such as collagen or PLGA.

The delivery medium used to deliver the therapeutic agent to thetreatment site can be suitably formulated to maintain or enhance theactivity of the therapeutic agent. For example, when the therapeuticagent comprises cellular material, the delivery medium can be formulatedto maintain cell function and viability.

Alternatively, the therapeutic agent can be contained within a mediumthat is coated on at least a portion of the surface of the device thatwill contact the tissue at the treatment site. For example, thetherapeutic agent can be contained within a suitable polymer coatingthat provides release of the therapeutic agent during treatment. In oneembodiment, at least a portion of the surface of the catheter that willcontact tissue is coated with a swellable hydrogel polymer coating asdescribed in U.S. Pat. No. 6,409,716 (“Drug Delivery,” Sahatjian et al.,co owned by the assignee of the present application, and incorporatedherein by reference in its entirety). As described therein, the hydrogelis a cross-linked polymer material formed from the combination of acolloid and water. Cross-linking reduces solubility and produces ajelly-like polymer that is characterized by the ability to swell andabsorb a substantial amount of the therapeutic agent of interest,typically in aqueous solution form. The hydrogel coating is alsoparticularly hydrophilic, water swellable, and lubricious. The aqueoustherapeutic agent solution can be effectively squeezed out of thecoating when pressure is applied by inflation of the balloon portions ofthe inventive catheter.

The present invention is not limited to the above-described preferredmethods, devices, systems and apparatuses. Furthermore, it should beunderstood that, while particular embodiments of the invention have beendiscussed, this invention is not limited thereto, as modifications canbe made by those skilled in the art, particularly in light of theforegoing teachings. Accordingly, the appended claims contemplatecoverage of any such modifications that incorporate the essentialfeatures of these improvements within the true spirit and scope of theinvention.

1. A catheter for insertion into a biological passage which contains afirst flowing fluid already in the biological passage, the cathetercomprising: a. a tubular member having a proximal end and a distal end;b. a fluid delivery lumen contained within the tubular member; c. aninflatable balloon assembly disposed at the distal end of the tubularmember, the balloon assembly including an inflatable balloon memberhaving an uninflated state and an inflated state, the balloon assemblyincluding apertures in communication with the fluid delivery lumen; d.an inflation lumen in communication with the balloon member; and e. avalve contained within the inflatable balloon assembly, the inflatableballoon assembly configured such that when the balloon member is in theinflated state: (i) sections of the balloon member contact thebiological passage defining at least one containment pocket; (ii) theapertures are disposed in the containment pocket, (iii) a flow lumen isdefined through the balloon member to allow the first fluid already inthe biological passage to flow through the balloon member; and (iv) thevalve functions to allow the first flowing fluid already in thebiological passage to flow through the flow lumen in a physiologicdirection, while blocking backflow of the first fluid through the flowlumen.
 2. The catheter according to claim 1 further comprising a guidewire lumen contained within the tubular member.
 3. The catheteraccording to claim 1 wherein the valve is a leaflet valve.
 4. Thecatheter according to claim 3 wherein the leaflet valve is inflatable.5. The catheter according to claim 3 wherein the leaflet valve comprisesthree leaflets.
 6. The catheter according to claim 3 wherein the leafletvalve comprises two leaflets.
 7. The catheter according to claim 1 wherethe valve is a ball valve.
 8. The catheter according to claim 7 whereinthe ball valve is inflatable.
 9. The catheter according to claim 1wherein the valve is a flap valve.
 10. The catheter according to claim 9wherein the flap valve is inflatable.
 11. The catheter according toclaim 1 further comprising a therapeutic agent containing mediumprovided to one or more of the containment pockets.
 12. The catheteraccording to claim 11 wherein the medium comprises a hydrogel.
 13. Thecatheter according to claim 11 wherein the medium comprises apolyacrylic acid.
 14. The catheter according to claim 11 wherein themedium comprises a copolymer of polylactic acid and polycaprolactone.15. The catheter according to claim 1 wherein the balloon assemblycomprises a single balloon attached to the tubular member to form ahelical configuration about the tubular member.
 16. A catheter forinsertion into a biological passage which contains a first flowingfluid, already in the biological passage, the catheter comprising: a. atubular member having a proximal end and a distal end; b. an inflatableballoon assembly disposed at the distal end of the tubular member, theballoon assembly including an inflatable balloon member having anuninflated state and an inflated state, c. an inflation lumen incommunication with the balloon member; d. a valve contained within theinflatable balloon assembly, the inflatable balloon assembly configuredsuch that when the balloon member is in the inflated state: (i) sectionsof the balloon member contact the biological passage defining at leastone containment pocket; (ii) a flow lumen is defined through the balloonmember to allow the first fluid already in the biological passage toflow through the balloon member; and (iii) the valve functions to allowthe first flowing fluid already in the biological passage to flowthrough the flow lumen in a physiologic direction, while blockingbackflow of the first fluid through the flow lumen.
 17. The catheteraccording to claim 16 wherein the inflation lumen is configured tocontain a medium comprising one or more therapeutic agents.
 18. Thecatheter according to claim 16 wherein the valve is a leaflet valve. 19.The catheter according to claim 18 wherein the leaflet valve isinflatable.
 20. The catheter according to claim 18 wherein the leafletvalve comprises three leaflets.
 21. The catheter according to claim 18wherein the leaflet valve comprises two leaflets.
 22. The catheteraccording to claim 16 where the valve is a ball valve.
 23. The catheteraccording to claim 22 wherein the ball valve is inflatable.
 24. Thecatheter according to claim 16 wherein the valve is a flap valve. 25.The catheter according to claim 24 wherein the flap valve is inflatable.26. A catheter for insertion into a biological passage which contains afirst flowing fluid already in the biological passage, the cathetercomprising: a. a tubular member having a proximal end and a distal end;b. a fluid delivery lumen contained within the tubular member; c. aninflatable balloon assembly comprising a first toroidal-shaped balloondisposed at the distal end of the tubular shaft, a secondtoroidal-shaped balloon spaced proximally from the first toroidal-shapedballoon, and a cylindrical sheath attached to the first and secondtoroidal-shaped balloons, wherein the first and second toroidal shapedballoons have an outer diameter, and wherein the sheath is attached tothe toroidal-shaped balloons at a position radially inward of the outerdiameter of the toroidal-shaped balloons; d. an inflation lumen incommunication with the toroidal-shaped balloons; e. a valve containedwithin the sheath, wherein the inflatable balloon assembly is configuredsuch that when the toroidal-shaped balloons are inflated: (i) thetoroidal-shaped balloons expand the sheath, (ii) sections of thetoroidal-shaped balloons contact the biological passage wall defining atleast one containment pocket between the biological passage, the tubularshaft, the toroidal-shaped balloons, and the sheath; (iii) the aperturesare disposed in the containment pocket, (iv) the sheath forms a flowlumen to allow the first fluid already in the biological passage to flowthrough the balloon member; and (v) the valve functions to allow thefirst flowing fluid already in the biological passage to flow throughthe flow lumen in a physiologic direction, while blocking backflow ofthe first fluid through the flow lumen.
 27. A method of delivering atherapeutic fluid to a treatment site in a biological passage, thetreatment site including a valve, the biological passage containing afirst fluid, the method comprising steps of: a. providing an inflatableballoon assembly on the distal end of a catheter, the size of theballoon assembly when deflated adapted to fit within the biologicalpassage; b. positioning the balloon assembly at the treatment site; c.inflating the balloon assembly at the treatment site; d. engaging asection of the biological passage with a section of the balloon assemblywhile maintaining a section of the balloon assembly away from thebiological passage thereby defining a plurality of containment pocketswithin the engaging section; e. delivering a therapeutic fluid to thecontainment pockets, wherein when the balloon assembly is inflated, theballoon assembly defines a flow lumen through which the first fluidalready in the biological passage can flow, while maintaining thetherapeutic fluid within the containment pockets, and a valve containedwithin the balloon assembly functions to allow the first flowing fluidalready in the biological passage to flow through the balloon member ina physiologic direction, while blocking backflow of the first fluidthrough the balloon member.
 28. The method according to claim 27 furthercomprising the step of inflating the valve after positioning the balloonassembly at the treatment site.